The following Compound (1):

(hereinafter “Compound (1)”), also known as faldaprevir, is known as a potent and selective inhibitor of HCV NS3 serine protease and falls within the scope of the acyclic peptide series of HCV inhibitors disclosed in U.S. Pat. Nos. RE 40,525, 7,514,557 and 7,585,845. Compound (1) is disclosed specifically as Compound #1055 in U.S. Pat. No. 7,585,845, and as Compound #1008 in U.S. Pat. No. 7,514,557. Preferred forms of Compound (1) include the crystalline forms, in particular the crystalline sodium salt form as described in U.S. Pat. No. 8,232,293. Compound (1), including the pharmaceutically acceptable salt forms thereof such as the sodium salt form, can be prepared according to the general procedures found in the above-cited references, all of which are herein incorporated by reference.
Compound (1) may also be known by the following alternate depiction of its chemical structure, which is equivalent to the above-described structure:

wherein B is
L0 is MeO—; L1 is Br; and R2 is
An existing formulation containing Compound (1) is a product in the form of a self-emulsifying drug delivery system (SEDDS) composition. The known SEDDS composition comprises a lipid-based pharmaceutical composition of the active suitable for oral administration via a liquid-filled capsule, and in particular a softgel capsule (see US Application Publication US 2011/0160149).
A disadvantage of these liquid SEDDS formulations is a propensity to form a specific genotoxic degradation product (hereinafter referred to as “Compound X.”) Compound X may be depicted by the following chemical structure showing the stereochemistry at the two chiral centers in this molecule:
Due to the high potential toxicity of the Compound X, the increase in this impurity over the product shelf life duration was deemed unacceptable from a regulatory perspective and thus there was an urgent need to solve this problem. For example, the EMEA (European Medicines Agency) Guideline on the Limits of Genotoxic Impurities (28 Jun. 2006) specifies a maximum intake value of 1.5 μg/day of a genotoxic impurity as being associated with an acceptable risk (1 in 100,000 increased cancer risk) for most marketed pharmaceuticals based on a lifetime exposure duration. For short duration treatment regimens higher levels of genotoxic impurities may be acceptable based on application of Haber's rule (fundamental concept in toxicology) to extrapolate acceptable limits for daily intake for shorter treatment durations (Fetter et al, Critical Reviews in Toxicology, 2011) without changing the associated level of cancer risk. For example, in its subsequent guidance document issued on 26 Jun. 2008, the EMEA's CHMP Safety Working Party indicated that the acceptable limits for daily intake of genotoxic impurities during clinical trials (1 in 1 million increased cancer risk plus an additional dose rate correction factor of 2) are 5, 10, 20, and 60 μg/day for a duration of exposure of 6-12 months, 3-6 months, 1-3 months, and less than 1 month, respectively. Since the treatment regimen with Compound (1) may be as short as 12 weeks (˜3 months) or 24 weeks (−6 months), maximum allowable intake values for Compound X may be as high as 20 μg/day (3 month regimen) or 10 μg/day (6 month regimen) when applying a 1 in 1 million increased cancer risk and a dose rate correction factor of 2. Taking into consideration the benefit of an approved marketed product, the maximum allowable intake values for Compound X may be as high as the calculated acceptable limit of 400 μg/day (3 month regimen) or 200 μg/day (6 month regimen) when applying a 1 in 100,000 increased cancer risk level. Thus, one goal of the present invention was to develop techniques to ensure that the maximum intake value of this degradation product would be maintained below these regulatory limits.
Prior to the discovery that Compound X was an Ames positive degradation product, the stability of Compound (1) NA drug products was controlled by standard product packaging (HDPE bottle with induction seal) and room temperature storage. Such conditions were considered sufficient to allow for the desired commercial product shelf life. As noted above, current regulatory requirements for controlling potentially genotoxic impurities limit such impurities to levels much lower than standard impurities. The discovery that Compound X was Ames positive and genotoxic required the development of further controls to insure the lowest possible levels of Compound X in the drug product for patient safety and to meet requirements of regulatory authorities.
While the level of the degradation product can be lessened by refrigerated storage of the liquid SEDDS product, such storage has its own cost and logistics disadvantages. The liquid form is also disadvantageous due to higher complexity in manufacture and due to the need to contain the liquid, such as by a capsule.
A solid dosage form is more preferred for manufacturing and product stability in transportation and storage.